EP2311799A1 - 4-Dedimethylamin-Tetracyclinverbindungen - Google Patents

4-Dedimethylamin-Tetracyclinverbindungen Download PDF

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Publication number
EP2311799A1
EP2311799A1 EP20100183331 EP10183331A EP2311799A1 EP 2311799 A1 EP2311799 A1 EP 2311799A1 EP 20100183331 EP20100183331 EP 20100183331 EP 10183331 A EP10183331 A EP 10183331A EP 2311799 A1 EP2311799 A1 EP 2311799A1
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EP
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Prior art keywords
group
dedimethylamino
substituted
alkyl
tetracycline
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EP20100183331
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English (en)
French (fr)
Inventor
Mark L. Nelson
Kwasi Ohemeng
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Paratek Pharmaceuticals Inc
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Paratek Pharmaceuticals Inc
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Publication of EP2311799A1 publication Critical patent/EP2311799A1/de
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    • C07F9/22—Amides of acids of phosphorus
    • C07F9/24—Esteramides
    • C07F9/2454—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/2475—Esteramides the amide moiety containing a substituent or a structure which is considered as characteristic of aralkylamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
    • C07C2603/44—Naphthacenes; Hydrogenated naphthacenes
    • C07C2603/46—1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines

Definitions

  • New tetracycline analogues have also been investigated which may prove to be equal to or more effective than the originally introduced tetracycline compounds. Examples include U.S. Patent Nos. 2,980,584 ; 2,990,331 ; 3,062,717 ; 3,165,531 ; 3,454,697 ; 3,557,280 ; 3,674,859 ; 3,957,980 ; 4,018,889 ; 4,024,272 ; and 4,126,680 . These patents are representative of the range of pharmaceutically active tetracycline and tetracycline analogue compositions.
  • tetracyclines were found to be highly effective pharmacologically against rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, inclusion conjunctivitis, and psittacosis.
  • tetracyclines became known as "broad spectrum" antibiotics.
  • the tetracyclines as a class rapidly became widely used for therapeutic purposes.
  • R 7 is a fused ring moiety of the formula where Q is C or a heteroatom; an acylfuranyl group; a tri-, tetra- or penta- halo substituted phenyl group; an aminomethylphenyl group; an acylaminomethyl group; an alkylesterphenyl group; an acylphenyl group; an acylalkynyl group; an acylalkoxyphenyl group; a methylphenyl group; a dimethylphenyl group; a carboxyphenyl group; a carboxyalkynyl group; a thiophene group; a halothiophene group; an alkoxycarbonylphenyl group; an alkoxyphenyl group; an alkoxyphenylalkynyl group; an alkoxypyridyl group
  • the invention pertains to 7, 9-substituted 4-dedimethylamino tetracycline compounds of Formula III: wherein: X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 2 and R 2' are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R 4 and R 4' are each independently alkyl, alkenyl, alkynyl, hydroxyl, halogen, hydrogen, or when taken together the oxygen of a carbonyl group; R 2' , R 3 , R 10 , R 11 and R 12 are each hydrogen or a pro-drug moiety; R 5 is hydroxyl, hydrogen, thiol, alkan
  • the invention pertains, at least in part, to 4-dedimethylamino tetracycline compounds of formula IV: wherein: X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 2 , R 7' and R 7" are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R 4 and R 4' are each independently alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy halogen, hydrogen, or taken together to form the oxygen of a carbonyl; R 2' , R 3 , R 10 , R 11 and R 12 are each hydrogen or a pro-drug moiety; R 5 is hydroxyl, hydrogen,
  • the invention also pertains, at least in part, to 9-substituted 4-dedimethylamino tetracycline compounds of the formula (V): wherein: R 7' and R 7" are each alkyl; and R 9 is a pyridylethynyl group; an alkenylcarbamate group; a halo group; an alkylacrylate group; a naphthyl group; a haloacetyl group; an alkyl carbamate group; a cyclopentyl or cyclopentenyl group; a benzofuranyl group; a phenylpropiononeamino group; a tosylamino group; a methoxypyridyl group; an alkeneamino group; an N-t-butyl group; a t-butylamide group; a hydroxybutylamino group; a hydroxypropylamino group; a phenyl group; a
  • the invention pertains to 13-substituted tetracycline compounds of the formula (VI): wherein: R 4 and R 4' are each independently alkyl, alkenyl, alkynyl, hydroxyl, halogen, hydrogen, or when taken together the oxygen of a carbonyl group; R 5 is hydrogen, hydroxyl, or a prodrug moiety; R 6 is an alkyl or an aryl group, and pharmaceutically acceptable salts, esters, and prodrugs thereof.
  • R 6 is a phenyl group, i.e., an alkoxyphenyl group, a halophenyl group, a carboxyphenyl group, an acylphenyl group, a cyanophenyl group, a nitrophenyl group, a naphthyl group, a dialkylphenyl group, or an alkylphenyl group; a t-butyl group; or an aminoalkanethio group.
  • a phenyl group i.e., an alkoxyphenyl group, a halophenyl group, a carboxyphenyl group, an acylphenyl group, a cyanophenyl group, a nitrophenyl group, a naphthyl group, a dialkylphenyl group, or an alkylphenyl group; a t-butyl group; or an aminoalkanethio group.
  • the invention pertains, at least in part, to 8-substituted 4-dedimethylamino tetracycline compounds of the formula: wherein: R 5 is hydrogen or hydroxyl; R 6 and R 6' are each independently hydrogen, methyl, or hydroxyl; R 7 is hydrogen, R 8 is phenyl, nitrophenyl, halo, or lower alkynyl; and R 9 is hydrogen or amino, and pharmaceutically acceptable salts, prodrugs and esters thereof.
  • the invention also pertains to a method for treating a tetracycline responsive state in a subject, by administering to the subject a 4-dedimethylamino tetracycline compound of the invention (e.g., of Formula I, II, III, IV, V, VI, VII, VIII or Table 2), such that the tetracycline responsive state is treated.
  • a 4-dedimethylamino tetracycline compound of the invention e.g., of Formula I, II, III, IV, V, VI, VII, VIII or Table 2
  • the tetracycline responsive state is not a bacterial infection.
  • the invention also includes pharmaceutical compositions comprising an effective amount of a 4-dedimethylamino tetracycline compound of the invention (e.g., of Formula I, II, III, IV, V, VI, VII, VIII or Table 2), and, optionally, a pharmaceutically acceptable carrier.
  • a 4-dedimethylamino tetracycline compound of the invention e.g., of Formula I, II, III, IV, V, VI, VII, VIII or Table 2
  • a pharmaceutically acceptable carrier e.g., of Formula I, II, III, IV, V, VI, VII, VIII or Table 2
  • the present invention pertains, at least in part, to novel 4-dedimethylamino tetracycline compounds.
  • These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as, but not limited to, bacterial infections and neoplasms, as well as other known applications for minocycline and tetracycline compounds in general, such as blocking tetracycline efflux and modulation of gene expression.
  • tetracycline compound includes many compounds with a similar ring structure to tetracycline.
  • examples of tetracycline compounds include: tetracycline, chlortetracycline, oxytetracycline, demeclocycline, methacycline, sancycline, doxycycline, and minocycline.
  • Other derivatives and analogues comprising a similar four ring structure are also included.
  • the term also includes 4-dedimethylamino tetracycline compounds. Table 1 depicts tetracycline and several known tetracycline derivatives. TABLE I
  • 7-substituted 4-dedimethylamino tetracycline compounds includes tetracycline compounds with substitution at the 7 position.
  • the substitution at the 7- position enhances the ability of the tetracycline compound to perform its intended function, e.g., treat tetracycline responsive states.
  • the 7-substituted tetracycline compound is 7-substituted 4-dedimethylamino tetracycline (e.g., wherein R 4 and R 4' are hydrogen, R 5 is hydrogen and X is CR 6 R 6' , wherein R 6 is methyl and R 6' is hydroxy); 7-substituted 4-dedimethylamino doxycycline (e.g., wherein R 4 and R 4' are hydrogen, R 5 is hydroxyl and X is CR 6 R 6' , wherein R 6 is methyl and R 6' is hydrogen); 7-substituted dedimethylamino tetracycline compounds, wherein X is CR 6 R 6' , R 4 , R 4' , R 5 , R 6' , and R 6 are hydrogen; or 7- substituted 4-dedimethylamino sancycline (wherein R 4 and R 4' are hydrogen; R 5 is hydrogen and X is
  • R 7 is not nitro or amino.
  • X is CR 6 R 6' ;
  • R 2 , R 2' , R 6 , R 6' , R 8 , R 9 R 10 R 11 , and R 12 are each hydrogen;
  • R 4 and R 4' are hydrogen, halogen (e.g., chlorine, fluorine, bromine, iodine, etc.), hydroxy, or when taken together the oxygen of a carbonyl group; and
  • R 5 is hydroxy or hydrogen.
  • R 7 is aryl.
  • aryl R 7 groups include substituted or unsubstituted phenyl.
  • the phenyl R 7 group can be substituted with any substituent which allow the tetracycline compound to perform its intended function.
  • substituents include, but are not limited to, alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio
  • the phenyl R 7 group is substituted with substituted or unsubstituted alkyl.
  • substituents of the alkyl include heterocycles such as, morpholine, piperdine, and pyrrolidine.
  • the phenyl R 7 group is substituted with an amino group.
  • the amino group also may be further substituted e.g., with an alkyl, alkenyl, alkynyl, carbonyl, alkoxy or aryl (e.g., substituted or unsubstituted, heteroaryl, phenyl, etc.) group.
  • the phenyl amino substituent may be substituted with any substituent or combination of substituents which allow it to perform its intended function.
  • substituents include halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), amino (e.g., which can in turn be substituted with an alkyl, carbonyl, alkenyl, alkynyl, or aryl moiety), and arylamino (e.g., phenylamino).
  • halogens e.g., fluorine, chlorine, bromine, iodine, etc.
  • amino e.g., which can in turn be substituted with an alkyl, carbonyl, alkenyl, alkynyl, or aryl moiety
  • arylamino e.g., phenylamino
  • the R 7 phenyl group may also be substituted with alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, perfluoromethoxy, perchloromethoxy, methylenedioxy, etc.
  • the phenyl group may also be substituted with an amide group such as a carbamate moiety (e.g., an alkoxycarbonylamino group).
  • the aryl group R 7 group also may be substituted or unsubstituted biaryl, e.g., naphthyl, fluorenyl, etc.
  • the biaryl R 7 group can be substituted with any substituent which allow it to perform its intended function.
  • substituents include but are not limited to, alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, aryl
  • the substituent is amino or formyl.
  • the aryl R 7 group also may be heteroaryl.
  • heteroaryl R 7 moieties include, but are not limited to, furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl, isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, and deazapurinyl.
  • the heteroaryl R 7 group is thiazolyl, thiophenyl, or furanyl.
  • R 7 also may be substituted or unsubstituted alkyl.
  • the alkyl group can be a straight or branched chain, e.g., methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl. etc.
  • the alkyl group may also comprise a ring, e.g., a cycloalkyl (e.g., cyclopentyl, cyclohexyl, cyclopropyl, or cyclobutyl).
  • the alkyl R 7 group may be substituted with any substituent or combination of substituents which allows the compound to perform its intended function.
  • substituents include, but are not limited to, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio,
  • the alkyl group is substituted with an amino, hydroxy, carboxy, carbonyl (e.g., substituted carbonyl, e.g., morpholinyl carbonyl), heterocyclic or aryl groups.
  • heterocyclic groups include, for example, furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyridinyl, pyrazolyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl, isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, and deazapurinyl.
  • the aryl e.g., substitute
  • the aralkyl R 7 group comprises substituted or unsubstituted phenyl.
  • This phenyl group also may be substituted with any substituent which allows it to perform its intended function. Examples of substituents include, but are not limited to, sulfonamido, alkyl, and the other substituents listed supra for alkyl R 7 groups.
  • R 7 also may be substituted or unsubstituted alkenyl.
  • substituents include those which allow the compound to perform its intended function. Examples of substituents include but are not limited to alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino
  • the alkenyl R 7 group is substituted with an aminocarbonyl (e.g., alkylaminocarbonyl, dialkylaminocarbonyl, dimethylaminocarbonyl) or alkoxycarbonyl.
  • an aminocarbonyl e.g., alkylaminocarbonyl, dialkylaminocarbonyl, dimethylaminocarbonyl
  • alkoxycarbonyl e.g., alkylaminocarbonyl, dialkylaminocarbonyl, dimethylaminocarbonyl
  • the alkenyl R 7 group also may be substituted with one or more halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxy groups, heteroaryl groups (e.g., furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyridinyl, pyrazolyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl, isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, deazapurinyl, etc.).
  • the heteroaryl substituent s thiazolyl.
  • the alkenyl R 7 group is substituted with a substituted or unsubstituted phenyl.
  • the phenyl can be substituted with any substituent which allows it to perform its intended function. Examples of substituents include those listed supra for other phenyl moieties.
  • substituents include, but are not limited to, halogens (e.g., fluorine, chlorine, bromine, iodine, etc.), alkoxy (e.g., methoxy, ethoxy, propoxy, perfluoromethyl, perchloromethyl, etc.), hydroxy, or alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.) groups.
  • halogens e.g., fluorine, chlorine, bromine, iodine, etc.
  • alkoxy e.g., methoxy, ethoxy, propoxy, perfluoromethyl, perchloromethyl, etc.
  • hydroxy hydroxy
  • alkyl e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.
  • R 7 include substituted and unsubstituted alkynyls.
  • the alkynyl moieties can be substituted with any substituent or combination of substituents which allow the tetracycline compound of the invention to perform its intended function.
  • substituents include, but are not limited to alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio,
  • the alkynyl R 7 moiety is substituted with an aryl, e.g., substituted or unsubstituted heteroaryl, phenyl, etc.
  • This aryl moiety may be substituted with any substituent or combinations of substituents listed supra for the alkynyl R 7 moiety.
  • advantageous substituents include, but are not limited to, carbonylamino (e.g., alkylcarbonylamino, dialkylcarbonylamino, arylcarbonylamino, etc.) and sulphonamido groups.
  • the alkynyl R 7 group is substituted with a tetracycline moiety.
  • tetracycline moiety includes a four ring tetracycline ring system as described above. This may be connected to the alkynyl R 7 group through a linker of 1-20 atoms. The linker may be attached to the tetracycline moiety at any position on that ring system which is convenient or allows the compound to perform its intended function. In a certain embodiment, the tetracycline moiety is attached to the linker at its 7 position.
  • R 7 moieties include substituted and unsubstituted alkylcarbonyl amino, sulfonamido, imino and carbonyl moieties.
  • the carbonyl moieties may be substituted with a substituted or unsubstituted alkyl group.
  • examples of possible substituents of the alkyl group include, but are not limited to, aryl moieties such as phenyl and heteroaryls (e.g., pyridinyl, etc.).
  • substituents of the imino group include, but are not limited to, hydroxy and alkoxy groups.
  • tetracycline compounds of the invention include compounds wherein R 7c is hydrogen, W' is oxygen and W is oxygen.
  • R 7a is substituted or unsubstituted phenyl.
  • substituents include, but are not limited to, alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, alkylcarbonylamino, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulf
  • R 7 is a fused ring moiety of the formula where Q is C or a heteroatom; an acylfuranyl group; a tri-, tetra- or penta- halo substituted phenyl group; an aminomethylphenyl group; an acylaminomethyl group; an alkylesterphenyl group; an acylphenyl group; an acylalkynyl group; an acylalkoxyphenyl group; a methylphenyl group; a dimethylphenyl group; a carboxyphenyl group; a carboxyalkynyl group; a thiophene group; a halothiophene group; an alkoxycarbonylphenyl group; an alkoxyphenyl group; an alkoxyphenylalkynyl group; an alkoxypyridyl group
  • 7-substituted 4-dedimethylamino sancycline compounds includes sancycline compounds with a substituent at the 7 position, as described in formula I and a substituent other than dimethylamino at the 4 position.
  • R 7 is a fused ring moiety of the formula where Q is C or a heteroatom.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(2'-benzofuran) 4-dedimethylamino sancycline.
  • R 7 is an acylfuranyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(3'-formylfuranyl) 4-dedimethylamino sancycline.
  • R 7 is a tri-, tetra- or penta- halo substituted phenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(2',3',4',5',6'-pentafluorophenyl) 4-dedimethylamino sancycline.
  • R 7 is an aminomethylphenyl 4-dedimethylamino group.
  • Examples of sancycline compounds with this R 7 substituent include 7-(4'-aminomethylphenyl) 4-dedimethylamino sancycline.
  • R 7 is an acylaminomethyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(4'-formylaminomethylphenyl) 4-dedimethylamino sancycline.
  • R 7 is an alkylesterphenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(4'-carboxyphenyl methylester) 4-dedimethylamino sancycline and 7-(2'-carboxyphenylethylester) 4-dedimethylamino sancycline.
  • R 7 is an alkylphenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(4'-tolyl) 4-dedimethylamino sancycline.
  • R 7 is an acylphenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(3'-formylphenyl) 4-dedimethylamino sancycline, 7-(4'-formylphenyl) 4-dedimethylamino sancycline, 7-(3'-acetylphenyl) 4-dedimethylamino sancycline, 7-(2'-acetylphenyl) 4-dedimethylamino sancycline, 7-(3'-acetylphenyl) 4-dedimethylamino sancycline, and 7-(4'-acetylphenyl) 4-dedimethylamino sancycline.
  • R 7 is an acylalkoxyphenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(3'-formyl-6'-methoxyphenyl) 4-dedimethylamino sancycline.
  • R 7 is a methylphenyl group.
  • Examples of sancycline compounds with this R 7 substituent include 7-(4'-methylphenyl) 4-dedimethylamino sancycline.
  • R 7 is a dimethylphenyl group.
  • Examples of sancycline compounds with this R 7 substituent include 7-(3',5'-dimethylphenyl) 4-dedimethylamino sancycline.
  • R 7 is a carboxyphenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(3'-carboxyphenyl) 4-dedimethylamino sancycline.
  • R 7 is a carboxyalkynyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(carboxyethynyl) 4-dedimethylamino sancycline.
  • R 7 is a thiophene group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(3-thiophene) 4-dedimethylamino sancycline, 7-(3'-methyl-2'-thiophene) 4-dedimethylamino sancycline, and 7-(3-methyl-5-thiophene) 4-dedimethylamino sancycline.
  • R 7 is a halothiophene group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(3'-chloro-2'-thiophene) 4-dedimethylamino sancycline and 7-(4'-chloro-2'-thiophene) 4-dedimethylamino sancycline.
  • R 7 is an alkoxycarbonylphenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(2'-ethoxycarbonylphenyl) 4-dedimethylamino sancycline.
  • R 7 is an alkoxyphenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(2'-ethoxyphenyl) 4-dedimethylamino sancycline, 7-(3'-ethoxyphenyl) 4-dedimethylamino sancycline, 7-(4'-methoxyphenyl) 4-dedimethylamino sancycline, and 7-(2',5'-dimethoxyphenyl) 4-dedimethylamino sancycline.
  • R 7 is an alkoxyphenylalkynyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(4'-methoxyphenylethynyl) 4-dedimethylamino sancycline.
  • R 7 is an alkoxypyridyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(4'-methoxy-5'-pyridyl) 4-dedimethylamino sancycline.
  • R 7 is a cyclopentyl or cyclopentenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(cyclopentenyl) 4-dedimethylamino sancycline.
  • R 7 is a cyclohexylalkynyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(cyclohexylethynyl) 4-dedimethylamino sancycline.
  • R 7 is a cyclohexenylalkynyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(1-ethynyl-1-cyclohexyl) 4-dedimethylamino sancycline.
  • R 7 is a cyclohexenylhaloalkenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(1-chlorovinyl-1-cyclohexyl) 4-dedimethylamino sancycline.
  • R 7 is a hydroxycyclohexylalkynyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(1-ethynyl-1-hydroxycyclohexyl) 4-dedimethylamino sancycline.
  • R 7 is a phenylalkynyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(phenylethynyl) 4-dedimethylamino sancycline, 7-(tolylethynyl) 4-dedimethylamino sancycline, and 7-(4-methoxyphenylethynyl) 4-dedimethylamino sancycline.
  • R 7 is a phenylalkenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(2-vinylpyridyl) 4-dedimethylamino sancycline and 7-(vinylphenyl) 4-dedimethylamino sancycline.
  • R 7 is an aminoalkynyl group.
  • Examples of 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(dimethylaminoethynyl) 4-dedimethylamino sancycline.
  • R 7 is a cyclobutylalkenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(cyclobutylmethenyl) 4-dedimethylamino sancycline.
  • R 7 is a pyridylalkynyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(2-pyridylethynyl) 4-dedimethylamino sancycline and 7-(3-pyridylethynyl) 4-dedimethylamino sancycline.
  • R 7 is a pyridylalkenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(4-pyridylethenyl) 4-dedimethylamino sancycline.
  • R 7 is a nitrophenylalkynyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(4-nitrophenylethynyl) 4-dedimethylamino sancycline.
  • R 7 is a nitrophenylalkenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(4-nitrostyryl) 4-dedimethylamino sancycline.
  • R 7 is an alkynyl group.
  • Examples of 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(ethynyl) 4-dedimethylamino sancycline.
  • R 7 is a cyanoalkynyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(cyano-1-pentynyl) 4-dedimethylamino sancycline.
  • R 7 is a cyanoalkenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include and 7-(cyanohexenyl) 4-dedimethylamino sancycline.
  • R 7 is a cyanophenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(3-cyanophenyl) 4-dedimethylamino sancycline and 7-(4-cyanophenyl) 4-dedimethylamino sancycline.
  • R 7 is a hydroxylphenylethynyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(3-hydroxylphenylethynyl) 4-dedimethylamino sancycline.
  • R 7 is a dialkylamidoalkenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(N,N-dimethylacrylamide) 4-dedimethylamino sancycline and 7-(dimethylamidoethenyl) 4-dedimethylamino sancycline.
  • R 7 is a dialkylamidophenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(3-dimethylamidophenyl) 4-dedimethylamino sancycline.
  • R 7 is an aminophenylethyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(4-aminophenylethyl) 4-dedimethylamino sancycline.
  • R 7 is an aminophenylethynyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(4-aminophenylethynyl) 4-dedimethylamino sancycline.
  • R 7 is a haloethenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(2-chloroethenyl) 4-dedimethylamino sancycline.
  • R 7 is a halophenylalkynyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(2-fluorophenylethenyl) 4-dedimethylamino sancycline.
  • R 7 is an alkylester-substituted pentenyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(1-iodo-1,3-dicarboethoxy-1,3-butadiene) 4-dedimethylamino sancycline.
  • R 7 is an aminophenylalkynyl group.
  • 4-dedimethylamino sancycline compounds with this R 7 substituent include 7-(4-aminophenylvinyl) 4-dedimethylamino sancycline.
  • the invention also pertains to the tetracycline compounds shown below:
  • the present invention pertains, at least in part, to novel 7,9- substituted 4-dedimethylamino tetracycline compounds.
  • These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for minocycline and tetracycline compounds in general, such as blocking tetracycline efflux and modulation of gene expression.
  • 7,9-substituted 4-dedimethylamino tetracycline compounds includes tetracycline compounds with substitution at the 7 and 9- positions and a substituent other than dimethylamino at the 4 position.
  • the substitution at the 7- and 9- positions enhances the ability of the tetracycline compound to perform its intended function, e.g., treat tetracycline responsive states.
  • the 7,9-substituted tetracycline compound is 7,9-substituted tetracycline (e.g., wherein R 4 is NR 4' R 4" ; R 4' and R 4" are methyl, R 5 is hydrogen and X is CR 6 R 6' , wherein R 6 is methyl and R 6' is hydroxy); 7,9-substituted doxycycline (e.g., wherein R 4 is NR 4' R 4" ; R 4' and R 4" are methyl, R 5 is hydroxyl and X is CR 6 R 6' , wherein R 6 is methyl and R 6' is hydrogen); or 7, 9- substituted sancycline (wherein R 4 is NR 4' R 4" ; R 4' and R 4" are methyl; R 5 is hydrogen and X is CR 6 R 6' wherein R 6 and R 6' are hydrogen atoms.
  • the 7, 9-substituted 4-dedimethylamino tetracycline compounds of the invention include compounds of Formula I: wherein: X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 2 and R 2' are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R 4 and R 4' are each independently alkyl, alkenyl, alkynyl, hydroxyl, halogen, hydrogen, or when taken together the oxygen of a carbonyl group; R 2' , R 3 , R 10 , R 11 and R 12 are each hydrogen or a pro-drug moiety; R 5 is hydroxyl, hydrogen, thiol, alkanoy
  • the tetracycline compounds of the invention include, for example, compounds wherein X is CR 6 R 6' ; R 4 and R 4' are hydrogen or the oxygen of a carbonyl group; R 2 , R 2' , R 6 , R 6' , R 8 , R 10 , R 11 , and R 12 are each hydrogen; R 4' and R 4" are lower alkyl; and R 5 is hydroxy or hydrogen. In an embodiment, R 4 and R 4' are each hydrogen and R 5 is hydrogen.
  • the tetracycline compounds of the invention include each possible combination of R 7 and R 9 substituents discussed below.
  • R 7 is aryl (e.g., heteroaryl or substituted or unsubstituted phenyl).
  • the phenyl R 7 group may be substituted with one or more substituents.
  • substituents of phenyl R 7 groups include alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phospho
  • the substituent is substituted or unsubstituted alkyl (e.g., methyl, ethyl, propyl, butyl, etc.), nitro, halogen (e.g., fluorine, bromine, chlorine, iodine, etc.), amino (e.g., unsubstituted amino, alkyl amino, dialkylamino (e.g., dimethylamino), or alkoxy (methylenedioxy or methoxy).
  • alkyl e.g., methyl, ethyl, propyl, butyl, etc.
  • nitro, halogen e.g., fluorine, bromine, chlorine, iodine, etc.
  • amino e.g., unsubstituted amino, alkyl amino, dialkylamino (e.g., dimethylamino), or alkoxy (methylenedioxy or methoxy).
  • R 7 also may be substituted or unsubstituted alkyl(e.g., methyl, ethyl, i-propyl, n-propyl, t-butyl, i-butyl, n-butyl, pentyl, n-pentyl, n-hexyl, or hexyl).
  • the alkyl may be branched or straight chain and may comprise a ring, e.g., a cycloalkyl ring, e.g., cyclohexyl ring.
  • the alkyl R 7 group may be substituted with any substituent which allows the tetracycline compound to perform its intended function.
  • substituents include, but are not limited to, alkenyl, halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl, alkoxy (e.g., methoxy, ethoxy, perchloromethoxy, perfluoromethoxy, etc.), alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, arylcarbonylamino, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylaminocarbonyl
  • heterocyclic substituents include N-isoindole-[1,3]-dione (e.g., phthalimide).
  • the substituent is arylcarbonylamino, e.g., heteroaryl carbonyl amino.
  • the heteroaryl group may be, for example, pyridinyl.
  • Other examples of substituents include amino or carboxylate.
  • R 7 is acyl, e.g., acetyl.
  • R 7 is substituted or unsubstituted alkynyl.
  • substituents include those which allow the tetracycline compound to perform its intended function.
  • substituents include, but are not limited to, alkyl (e.g., methyl, ethyl, propyl, butyl, etc.), alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, arylcarbonylamino, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylaminocarbonyl, alkylcarbonyl, alkoxycarbonyl,
  • the aryl substituent is substituted or unsubstituted phenyl.
  • the phenyl also may be further substituted with one or more substituents which allow the compound to perform its intended function.
  • substituents include, but are not limited to, alkoxy (e.g., methoxy).
  • the tetracycline compounds of the invention include compounds wherein R 9 is substituted or unsubstituted aryl (e.g., carbocyclic or heteroaryl). In an embodiment, R 9 is substituted or unsubstituted phenyl.
  • the substituted phenyl group can be substituted with any substituent or combination of substituents which allows the compound to perform its intended function.
  • substituents include, but are not limited to, alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio
  • the phenyl R 9 substituent is substituted or unsubstituted alkyl, nitro, halogen, amino, or alkoxy (e.g., methylenedioxy).
  • the invention also includes compounds wherein R 9 is substituted or unsubstituted alkyl (e.g., methyl, ethyl, i-propyl, n-propyl, i-butyl, t-butyl, n-butyl, pentyl, hexyl, etc.).
  • alkyl e.g., methyl, ethyl, i-propyl, n-propyl, i-butyl, t-butyl, n-butyl, pentyl, hexyl, etc.
  • substituents include, but are not limited to, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, arylcarbonylamino, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, alkylcarbonylamino, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkyl,
  • the R 9 group is aminomethyl.
  • the alkyl R 9 group is substituted with arylcarbonylamino (e.g., heteroarylcarbonylamino, e.g., pyridinylcarboynlamino) or alkylcarbonylamino.
  • the R 9 alkyl group is substituted with a heterocyclic substituent, such as isoindole-[1,3]-dione (e.g., phthalimide).
  • a heterocyclic substituent such as isoindole-[1,3]-dione (e.g., phthalimide).
  • R 7 is acyl, e.g., acetyl.
  • R 9 is substituted or unsubstituted alkynyl.
  • the alkynyl R 9 group can be substituted with any substituent which allows the tetracycline compound of the invention to perform its intended function.
  • substituents include, but are not limited to, alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, etc.), alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, arylcarbonylamino, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl,
  • the aryl substituted alkynyl R 9 moiety is, for example, substituted or unsubstituted phenyl.
  • the phenyl may be substituted with, for example, alkoxy, e.g., methoxy.
  • alkenyl substituents include cycloalkenes such as, cyclohexene.
  • R 9 is not unsubstituted phenyl when R 7 is unsubstituted phenyl.
  • 7,9-substituted 4-dedimethylamino tetracycline compounds of the invention include those listed below and in Table 2:
  • the invention also pertains to each of the 4-dedimethylamino tetracycline compounds shown in Table 2, as well as their pharmaceutically acceptable salts, esters, and prodrugs.
  • the present invention pertains, at least in part, to novel 9- substituted 4-dedimethylamino tetracycline compounds.
  • These tetracycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for tetracycline compounds, such as blocking tetracycline efflux and modulation of gene expression.
  • 9-substituted 4-dedimethylamino tetracycline compounds includes tetracycline compounds with substitution at the 9 position.
  • the substitution at the 9- position enhances the ability of the tetracycline compound to perform its intended function, e.g., treat tetracycline responsive states.
  • the 9-substituted tetracycline compound is 9-substituted 4-dedimethylamino tetracycline (e.g., wherein R 4 and R 4' are hydrogen, R 5 is hydrogen and X is CR 6 R 6' , wherein R 6 is methyl and R 6' is hydroxy); 9-substituted 4-dedimethylamino doxycycline (e.g., wherein R 4 and R 4' are hydrogen, R 5 is hydroxyl and X is CR 6 R 6' , wherein R 6 is methyl and R 6' is hydrogen); 9-substituted dedimethylamino minocycline compounds, wherein X is CR 6 R 6' , R 4 , R 4' , R 5 , R 6' , and R 6 are hydrogen, and R 7 is dimethylamino; or 9- substituted 4-dedimethylamino sancycline (wherein R 4 and R 4' are hydrogen;
  • the invention pertains, at least in part, to tetracycline compounds of Formula IV: wherein: X is CHC(R 13 Y'Y), CR 6' R 6 , S, NR 6 , or O; R 2 , R 7' and R 7" are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; R 4 and R 4' are each independently alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy halogen, hydrogen, or taken together to form the oxygen of a carbonyl; R 2' , R 3 , R 10 , R 11 and R 12 are each hydrogen or a pro-drug moiety; R 5 is hydroxyl, hydrogen, thiol, alkanoy
  • tetracycline compounds refers to compounds of formula (I) above.
  • the term minocycline compounds include compounds wherein X is CR 6 R 6' ; R 2 , R 2' , R 5 , R 6 , R 6' , R 8 , R 9 , R 10 , R 11 , and R 12 are each hydrogen; R 7 is NR 7' R 7" ; R 4 and R 4' are each hydrogen or taken together to form the oxygen of a carbonyl group; and R 7' , and R 7" are each lower alkyl, e.g., methyl.
  • R 9 examples include substituted and unsubstituted aryl groups.
  • the aryl groups include substituted and unsubstituted heteroaryls (e.g., furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl, isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, or deazapurinyl), substituted or unsubstituted phenyl, and groups with more than one aromatic ring, such as naphthyl.
  • heteroaryls e.g., furanyl, imi
  • substituents of R 9 include, but are not limited to, alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thiocarboxylate, alkyl
  • the aryl R 9 group is substituted with one or more substituents such as, for example, carboxylate, alkyl, alkenyl, alkynyl, aryl, heterocyclic, cyano, amino, halogen, alkoxy, alkoxycarbonyl, amido, alkylcarbonyl, or nitro.
  • substituents such as, for example, carboxylate, alkyl, alkenyl, alkynyl, aryl, heterocyclic, cyano, amino, halogen, alkoxy, alkoxycarbonyl, amido, alkylcarbonyl, or nitro.
  • R 9 is substituted or unsubstituted alkynyl.
  • the alkynyl R 9 group may be substituted with a substituted or unsubstituted aryl group, such as, for example, phenyl.
  • the possible substituents for the substituted phenyl group include, for example, those listed supra, for the aryl R 9 group.
  • the substituted alkynyl R 9 group may be substituted with a heteroaryl (e.g., pyridinyl), alkyl (e.g.
  • alkenyl e.g. , ethenyl, propenyl, butenyl, pentenyl, hexenyl, etc.
  • carboxylate silyl (e.g. , trialkylsilyl, e.g. , trimethylsilyl), aralkyl, or a alkyloxycarbonyl group.
  • Each of these groups may also be further substituted, with such substituents as alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio, thio
  • the alkynyl R 9 group is substituted with an aminoalkyl group.
  • the aminoalkyl group may then also be substituted with, for example, an alkyl, alkenyl, alkynyl, acyl, carbonyl, or alkylsulfone group.
  • the alkynyl R 9 group is substituted with a cycloalkenyl group, such as, for example, cyclopentene.
  • R 9 is alkyl.
  • the alkyl group may be substituted or unsubstituted.
  • alkyl groups include, for example, both straight chain, branched and cyclic alkyl groups.
  • alkyl groups include methyl, ethyl, i-propyl, n-propyl, i-butyl, n-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.
  • Cyclic alkyl groups include groups with one or more rings, such as, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc .
  • the alkyl R 9 group is 2-cyclopentylethyl.
  • substituents of alkyl groups include, for example, halogens (e.g. , fluorine, chlorine, bromine, iodine, etc .), hydroxyl, alkoxy ( e.g. , methoxy, ethoxy, propoxy, butoxy, pentoxy, perfluoromethoxy, perchloromethoxy, etc .), alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, carboxy, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino, amino
  • R 9c include hydrogen.
  • Z' may be, for example, S, NH, or O.
  • Z include NR 9b ( e.g. , when R 9b is hydrogen, alkyl, etc .), O or S.
  • R 9a groups include aryl groups such as substituted and unsubstituted phenyl.
  • substituents of aryl R 9a groups include, but are not limited to, alkyl (e.g. , methyl, ethyl, propyl, butyl, pentyl, hexyl, perfluormethyl, perchloroethyl, etc .), alkenyl, halogen (e.g. , fluorine, chlorine, bromine, iodine, etc .), hydroxyl, alkoxy ( e.g.
  • At least one of the substituents of the substituted phenyl is nitro, alkoxy (e.g. , methoxy, methylenedioxy, perfluoromethoxy) alkyl ( e.g. , methyl, ethyl, propyl, butyl, or pentyl), acetyl, halogen ( e.g. , fluorine, chlorine, bromine, or iodine), or amino ( e.g. , dialkylamino).
  • the alkoxy group is perhalogenated, e.g. , perfluoromethoxy.
  • aryl R 9a groups include, but are not limited to, unsubstituted phenyl, para -nitrophenyl, para -methoxy phenyl, para -perfluoromethoxy phenyl, para- acetyl phenyl, 3, 5-methylenedioxyphenyl, 3,5-diperfluoromethyl phenyl, para-bromo phenyl, para -chloro phenyl, and para-fluoro phenyl.
  • aryl R 9a groups include substituted and unsubstituted heterocycles (e.g. , furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, pyrolidinyl, oxazolyl, isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, or deazapurinyl) and substituted and unsubstituted biaryl groups, such as naphthyl and fluorene.
  • substituted and unsubstituted heterocycles e.g. , furanyl, imidazolyl, be
  • R 9a also may be substituted or unsubstituted alkyl, e.g. , methyl, ethyl, propyl, butyl, pentyl, etc .
  • substituents include but are not limited to halogens (e.g. , fluorine, bromine, chlorine, iodine, etc .), hydroxyl, alkoxy ( e.g. , methoxy, ethoxy, propoxy, butoxy, etc.
  • R 9a also can be substituted or unsubstituted alkenyl.
  • substituents for alkenyl R 9a groups include those listed above for alkyl R 9a groups.
  • alkenyl R 9a groups include pent-1-enyl.
  • Z' is NH
  • Z is NH
  • R 9a is alkyl
  • R 9 is aminoalkyl (e.g ., aminomethyl).
  • Aminoalkyl R 9 groups may be further substituted.
  • substituents include aryl groups, such as, for example substituted or unsubstituted phenyl ( e.g. , methylenedioxyphenyl or para -perfluoromethoxyphenyl), or heteroaromatic groups which allows the compound of the invention to perform its intended function.
  • tetracycline compounds of the invention include those listed in Table 2, as well as the ones listed below:
  • the invention also relates, at least in part, to 9-substituted 4-dedimethylamino minocycline compounds of the formula: wherein: R 7' , and k 7" are each alkyl; and R 9 is a pyridylethynyl group; an alkenylcarbamate group; a halo group; an alkylacrylate group; a naphthyl urea group; a haloacetyl group; an alkyl carbamate group; a cyclopentyl or cyclopentenyl group; a benzofuranyl group; a phenylpropiononeamino group; a tosylamino group; a methoxypyridyl group; an alkeneamino group; an N-t-butyl group; a t-butylamide group; a hydroxybutylamino group; a hydroxypropylamino group; a phenyl group;
  • 9-substituted 4-dedimethylamino minocycline compound includes minocycline compounds with a substituent at the 9 position and a substituent other than dimethylamino at the 4 position.
  • the compound is a derivative of minocycline.
  • R 9 is an alkenylcarbamate group.
  • minocycline compounds with this R 9 substituent include 9-isopropenyl carbamate 4-dedimethylamino minocycline.
  • R 9 is a pyridylethynyl group.
  • minocycline compounds with this R 9 substituent include 9-(2-pyridylethynyl) 4-dedimethylamino minocycline.
  • R 9 is a halo group.
  • minocycline compounds with this R 9 substituent include 9-iodo 4-dedimethylamino minocycline.
  • R 9 is an alkylacrylate group.
  • minocycline compounds with this R 9 substituent include 9-butylacrylate 4-dedimethylamino minocycline.
  • R 9 is a naphthyl urea group.
  • minocycline compounds with this R 9 substituent include 9-naphthyl 4-dedimethylamino minocycline urea.
  • R 9 is a haloacetyl group.
  • minocycline compounds with this R 9 substituent include 9-chloroacetyl 4-dedimethylamino minocycline urea.
  • R 9 is an alkyl carbamate group.
  • Examples of minocycline compounds with this R 9 substituent include 9-neopentyl 4-dedimethylamino minocycline carbamate.
  • R 9 is a cyclopentyl or cyclopentenyl group.
  • minocycline compounds with this R 9 substituent include 9-cyclopentene 4-dedimethylamino minocycline.
  • R 9 is a benzofuranyl group.
  • minocycline compounds with this R 5 substituent include 9-benzofuranyl 4-dedimethylamino minocycline.
  • R 9 is a phenylpropiononeamino group.
  • minocycline compounds with this R 9 substituent include 9-(phenylpropiononeamino) 4-dedimethylamino minocycline.
  • R 9 is a tosylamino group.
  • minocycline compounds with this R 9 substituent include 9-tosylamino 4-dedimethylamino minocycline.
  • R 9 is a methoxypyridyl group.
  • minocycline compounds with this R 5 substituent include 9-(2-methoxy-3-pyridyl) 4-dedimethylamino minocycline.
  • R 5 is an alkeneamino group.
  • minocycline compounds with this R 9 substituent include 9-(N-2'-hydroxydecyl-9'-ene-amino) 4-dedimethylamino minocycline.
  • R 9 is an N-t-butyl group.
  • minocycline compounds with this R 9 substituent include N-t-butyl-4-dedimethylamino minocycline HCl.
  • R 9 is a t-butylamide group.
  • minocycline compounds with this R 9 substituent include 9-BOC-NH 4-dedimethylamino minocycline.
  • R 9 is a hydroxybutylamino group.
  • minocycline compounds with this R 9 substituent include 9-(N-2'-hydroxybutylamino) 4-dedimethylamino minocycline.
  • R 9 is a hydroxypropylamino group.
  • minocycline compounds with this R 9 substituent include 9-(N-3-chloro, 2-hydroxylpropylamino) 4-dedimethylamino minocycline.
  • R 9 is a phenyl group.
  • minocycline compounds with this R 9 substituent include 9-phenyl 4-dedimethylamino minocycline HCl and 9-p-tolyl 4-dedimethylamino minocycline.
  • R 9 is a nitrophenyl group.
  • minocycline compounds with this R 9 substituent include 9-(3'-nitrophenyl) 4-dedimethylamino minocycline.
  • R 9 is a nitrophenyl alkynyl group.
  • minocycline compounds with this R 9 substituent include 9-(4'-nitrophenylethynyl) 4-dedimethylamino minocycline.
  • R 9 is an aminophenyl group.
  • Examples of minocycline compounds with this R 9 substituent include 9-(3-aminophenyl) 4-dedimethylamino minocycline.
  • R 9 is a halophenyl urea group;.
  • minocycline compounds with this R 9 substituent include 9-(4-chloro,2-trifluoromethylphenyl) 4-dedimethylamino minocycline urea.
  • R 9 is an alkoxyphenyl group.
  • minocycline compounds with this R 9 substituent include 9-(p-methoxyphenyl) 4-dedimethylamino minocycline, 9-(4'-methoxyphenyl) 4-dedimethylamino minocycline, and 9-(3,4-methylenedioxyphenyl) 4-dedimethylamino minocycline.
  • R 9 is a cyanophenyl group.
  • minocycline compounds with this R 9 substituent include 9-(4'-cyanophenyl) 4-dedimethylamino minocycline.
  • R 9 is a carboxyalkylphenyl group.
  • minocycline compounds with this R 9 substituent include 9-(4'-carboxyphenyl) 4-dedimethylamino minocycline.
  • R 9 is an acylphenyl group.
  • minocycline compounds with this R 9 substituent include 9-(3-formylphenyl) 4-dedimethylamino minocycline.
  • R 9 is an alkylphenyl group.
  • Examples of minocycline compounds with this R 9 substituent include 9-(4'-t-butylphenyl) 4-dedimethylamino minocycline.
  • R 9 is a halophenyl group.
  • minocycline compounds with this R 9 substituent include 9-(3-chlorophenyl) 4-dedimethylamino minocycline, 9-(2',4'-difluorophenyl) 4-dedimethylamino minocycline, 9-(3,4-difluorophenyl) 4-dedimethylamino minocycline, 9-(4'-chlorophenyl) 4-dedimethylamino minocycline, 9-(3,4-dichlorophenyl) 4-dedimethylamino minocycline, and 9-(4'-trifluoromethylphenyl) 4-dedimethylamino minocycline.
  • R 9 is an alkoxyphenyl group.
  • Examples of minocycline compounds with this R 9 substituent include 9-(3-ethoxyphenyl) 4-dedimethylamino minocycline.
  • R 9 is a carboxyalkylphenyl group.
  • minocycline compounds with this R 9 substituent include 9-(4-carboxymethylphenyl) 4-dedimethylamino minocycline.
  • R 9 is a phenylalkynyl group.
  • minocycline compounds with this R 9 substituent include 9-(phenylethynyl) 4-dedimethylamino minocycline, 9-(3-hydroxyphenylethynyl) 4-dedimethylamino minocycline, 9-(p-tolylethynyl) 4-dedimethylamino minocycline, and 9-(p-methoxyphenylethynyl) 4-dedimethylamino minocycline.
  • R 9 is an alkynyl group.
  • minocycline compounds with this R 9 substituent include 9-ethynyl 4-dedimethylamino minocycline, 9-(p-fluoroethynyl) 4-dedimethylamino minocycline, 9-(trimethylsilylethynyl) 4-dedimethylamino minocycline, 9-(propionyl) 4-dedimethylamino minocycline, 9-(cyclohexenylethynyl) 4-dedimethylamino minocycline, and 9-(1-cyclohexyl-1-hydroxyethynyl) 4-dedimethylamino minocycline.
  • R 9 is an alkylglycineethylester group.
  • minocycline compounds with this R 9 substituent include 9-propylglycineethylester 4-dedimethylamino minocycline HCl, and 9-methylglycineethylester 4-dedimethylamino minocycline.
  • R 9 is a styrene group.
  • minocycline compounds with this R 9 substituent include 9-(styrene) 4-dedimethylamino minocycline, 9-(4'-fluorostyrene) 4-dedimethylamino minocycline.
  • R 9 is a thiophene group.
  • minocycline compounds with this R 9 substituent include 9-(2-thiophene) 4-dedimethylamino minocycline, and 9-(5'-chloro-2'-thiophene) 4-dedimethylamino minocycline.
  • R 9 is an alkylaminophospho group.
  • minocycline compounds with this R 9 substituent include 9-(p-methoxyphenylaminophospho) 4-dedimethylamino minocycline, and 9-(phenylaminophospho) 4-dedimethylamino minocycline.
  • the invention pertains to 13-substituted 4-dedimethylamino tetracycline compounds of the formula: wherein: R 4 and R 4' are each independently alkyl, alkenyl, alkynyl, hydroxyl, halogen, hydrogen, or when taken together the oxygen of a carbonyl group; R 5 is hydrogen, hydroxyl, or a prodrug moiety; R 6 is an alkyl or an aryl group, and pharmaceutically acceptable salts, esters, and prodrugs thereof.
  • 13-substituted 4-dedimethylamino tetracycline compounds includes 4-dedimethylamino methacycline compounds with a substituent at the 13 position (e.g., a compound of formula I with a substituent at the R 6 position).
  • the 13-substituted 4-dedimethylamino methacycline compound is 13-substituted 4-dedimethylamino methacycline (e.g., wherein R 4 and R 4' are hydrogen, and R 5 is hydroxyl).
  • R 4 and R 4' taken together are the oxygen of a carbonyl group.
  • R 6 is a phenyl group, i.e., an alkoxyphenyl group, a halophenyl group, a carboxyphenyl group, an acylphenyl group, a cyanophenyl group, a nitrophenyl group, a naphthyl group, a dialkylphenyl group, or an alkylphenyl group; a t-butyl group; or an aminoalkanethio group.
  • a phenyl group i.e., an alkoxyphenyl group, a halophenyl group, a carboxyphenyl group, an acylphenyl group, a cyanophenyl group, a nitrophenyl group, a naphthyl group, a dialkylphenyl group, or an alkylphenyl group; a t-butyl group; or an aminoalkanethio group.
  • R 6 is a phenyl group, i.e., an alkoxyphenyl group, an halophenyl group, a carboxyphenyl group, an acylphenyl group, a cyanophenyl group, a nitrophenyl group, a naphthyl group or an alkylphenyl group; a t-butyl group; an aminoalkanethio group.
  • R 6 is a phenyl group include 13-(phenyl) 4-dedimethylamino methacycline and 13-(4'-chlorophenyl-5-cyclohexanoate) 4-dedimethylamino methacycline.
  • R 6 is an alkoxyphenyl group.
  • examples of such compounds include 13-(4'-methoxyphenyl) 4-dedimethylamino methacycline, 13-(methylenedioxyphenyl) 4-dedimethylamino methacycline, 13-(4'-ethoxyphenyl) 4-dedimethylamino methacycline, 13-(p-carbomethoxyphenyl) 4-dedimethylamino methacycline, and 13-(3',4'-methylenedioxyphenyl) 4-dedimethylamino methacycline.
  • R 6 is a halophenyl group.
  • examples of such compounds include 13-(4'-fluorophenyl) 4-dedimethylamino methacycline, 13-(4'-chlorophenyl) 4-dedimethylamino methacycline, 13-(3'-chlorophenyl) 4-dedimethylamino methacycline, 13-(methylenedioxyphenyl) 4-dedimethylamino methacycline, 13-(3'-carboxylphenyl) 4-dedimethylamino methacycline, 13-(3'-4'-dichlorophenyl) 4-dedimethylamino methacycline, 13-(4'-acetylphenyl) 4-dedimethylamino methacycline, 13-(4'-ethoxyphenyl) 4-dedimethylamino methacycline, 13-(4'-chlorophenyl-5-
  • R 6 is a carboxyphenyl group.
  • examples of such compounds include 13-(3'-carboxylphenyl) 4-dedimethylamino methacycline.
  • R 6 is an acylphenyl group.
  • examples of such compounds include 13-(3'-acetylphenyl) 4-dedimethylamino methacycline, 13-(4'-acetylphenyl) 4-dedimethylamino methacycline, and 13-(3'-formyl) 4-dedimethylamino methacycline.
  • R 6 is a cyanophenyl group.
  • examples of such compounds include 13-(p-cyanophenyl) 4-dedimethylamino methacycline.
  • R 6 is a nitrophenyl group.
  • examples of such compounds include 13-(4'-nitrophenyl) 4-dedimethylamino methacycline.
  • R 6 is a naphthyl group.
  • examples of such compounds include 13-(naphthyl) 4-dedimethylamino methacycline.
  • R 6 is an dialkylphenyl group.
  • examples of such compounds include 13-(3,5-dimethylphenyl) 4-dedimethylamino methacycline.
  • R 6 is an alkylphenyl group.
  • examples of such compounds include 13-(p-t-butylphenyl) 4-dedimethylamino methacycline and 13-(p-tolyl) 4-dedimethylamino methacycline.
  • R 6 is a t-butyl group.
  • examples of such compounds include 9,13-di-t-butyl) 4-dedimethylamino methacycline.
  • R 6 is an aminoalkanethio group.
  • examples of such compounds include 13-(dimethylaminoethanethio) 4-dedimethylamino methacycline.
  • Examples of 13-substituted methacycline compounds include 13-(phenyl) 4-dedimethylamino methacycline, 13-(4'-chlorophenyl-5-cyclohexanoate) 4-dedimethylamino methacycline, 13-(4'-methoxyphenyl) 4-dedimethylamino methacycline, 13-(methylenedioxyphenyl) 4-dedimethylamino methacycline, 13-(4'-ethoxyphenyl) 4-dedimethylamino methacycline, 13-(p-caxbomethoxyphenyl) 4-dedimethylamino methacycline, 13-(3',4'-methylenedioxyphenyl) 4-dedimethylamino methacycline, 13-(4'-fluorophenyl) 4-dedimethylamino methacycline, 13-(4'-chlorophenyl) 4-de
  • 8-substituted 4-dedimethylamino tetracycline compounds includes tetracycline compounds with a substituent at the 8 position, as described in formula I, and a substituent other than dimethylamino at the 8 position.
  • the substituted tetracycline compound is a substituted 4-dedimethylamino doxycycline derivative (e.g., wherein R 4 and R 4' are hydrogen, R 5 is hydroxyl, R 6 is methyl, and R 6' is hydrogen).
  • X is CR 6 R 6' ;
  • R 2 , R 2' , R 6 , R 6' , R 8 , R 9 , R 10 , R 11 , and R 12 are each hydrogen;
  • R 4 and R 4' are hydrogen, halogen (e.g., chlorine, fluorine, bromine, iodine, etc.), hydroxy, or when taken together the oxygen of a carbonyl group; and
  • R 5 is hydroxy or hydrogen.
  • R 4 , R 4' , and R 5 are each hydrogen;
  • R 7 is hydrogen; and
  • R 9 is hydrogen or amino.
  • R 8 is halogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl. R 8 may be further substituted or unsubstituted.
  • R 8 is aryl.
  • aryl R 8 groups include substituted or unsubstituted phenyl.
  • the phenyl R 8 group can be substituted with any substituent which allow the tetracycline compound to perform its intended function.
  • substituents include, but are not limited to, alkyl, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio
  • the aryl R 8 group also may be heteroaryl.
  • heteroaryl R 8 moieties include, but are not limited to, furanyl, imidazolyl, benzothiophenyl, benzofuranyl, quinolinyl, isoquinolinyl, pyridinyl, pyrazolyl, benzodioxazolyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, methylenedioxyphenyl, indolyl, thienyl, pyrimidyl, pyrazinyl, purinyl, pyrazolyl, oxazolyl, isooxazolyl, naphthridinyl, thiazolyl, isothiazolyl, and deazapurinyl.
  • the heteroaryl R 7 group is thiazolyl, thiophenyl, or furanyl.
  • R 8 also may be substituted or unsubstituted alkyl.
  • the alkyl group can be a straight or branched chain, e.g., methyl, ethyl, i-propyl, n-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl. etc.
  • the alkyl group may also comprise a ring, e.g., a cycloalkyl (e.g., cyclopentyl, cyclohexyl, cyclopropyl, or cyclobutyl).
  • the alkyl R 8 group may be substituted with any substituent or combination of substituents which allows the compound to perform its intended function.
  • substituents include, but are not limited to, alkenyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio,
  • R 8 also may be substituted or unsubstituted alkenyl.
  • substituents include those which allow the compound to perform its intended function. Examples of substituents include but are not limited to alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino
  • R 8 include substituted and unsubstituted alkynyls.
  • the alkynyl moieties can be substituted with any substituent or combination of substituents which allow the tetracycline compound of the invention to perform its intended function.
  • substituents include, but are not limited to alkyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, alkyloxycarbonyl, carboxy, arylcarbonyloxy, alkoxycarbonylamino, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aminoalkyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, silyl, aminocarbonyl, alkylthiocarbonyl, phosphate, aralkyl, phosphonato, phosphinato, cyano, amino, acylamino, amido, imino, sulfhydryl, alkylthio, sulfate, arylthio,
  • the invention pertains to, at least in part, to 8-substituted tetracycline compounds of the formula (VIII): wherein: R 5 is hydrogen or hydroxyl; R 6 and R 6' are each independently hydrogen, methyl, or hydroxyl; R 7 is hydrogen, R 8 is phenyl, nitrophenyl, halo, or lower alkynyl; and R 9 is hydrogen or amino, and pharmaceutically acceptable salts, prodrugs and esters thereof.
  • R 5 is hydrogen or hydroxyl
  • R 6 and R 6' are each independently hydrogen, methyl, or hydroxyl
  • R 7 is hydrogen
  • R 8 is phenyl, nitrophenyl, halo, or lower alkynyl
  • R 9 is hydrogen or amino, and pharmaceutically acceptable salts, prodrugs and esters thereof.
  • doxycycline derivatives of tetracycline compounds of the invention include compounds wherein R 7 is hydrogen, R 8 is halo, phenyl, or nitrophenyl, and R 9 is hydrogen.
  • R 7 is hydrogen
  • R 8 is phenyl or lower alkynyl (e.g., ethynyl)
  • R 9 is amino.
  • Examples of such tetracycline compounds which are doxycycline derivatives include 8-phenyl 4-dedimethylamino doxycycline, 8-bromo 4-dedimethylamino doxycycline, 8-( p -nitrophenyl) 4-dedimethylamino doxycycline, 8-ethynyl-9-amino 4-dedimethylamino doxycycline, and 8-phenyl-9-amino 4-dedimethylamino doxycycline.
  • tetracycline compounds of this invention can be synthesized using the methods described in the Schemes and Examples below.
  • Certain substituted 4-dedimethylamino tetracycline compounds can be synthesized by the method shown in Scheme 1. Although in each scheme sancycline is used as the tetracycline compound, one of skill in the art will appreciate that the methodology can also be applied to other tetracycline compounds such as tetracycline and doxycycline. In addition, similar methodology can be used to synthesize 9-substituted 4-dedimethylamino tetracycline compounds.
  • substituted 4-dedimethylamino tetracycline compounds can be synthesized as shown in Scheme 1 for 4-dedimethylamino sancycline.
  • 4-Dedimethylamino sancycline (1A) is treated with sulfuric acid and sodium nitrate.
  • the resulting product is 7-nitro (1B) 4-dedimethylamino sancycline (in a mixture with the 9-position isomers).
  • the nitro 4-dedimethylamino sancycline compound is then treated with hydrogen gas and a platinum catalyst to yield the 7-amino 4-dedimethylamino sancycline compound, 1C.
  • the 7-amino 4-dedimethylamino sancycline compound is treated with HONO, to yield the diazonium salt (1D).
  • the salt can subsequently be treated with numerous compounds possessing an alkene or II bond functional group such as alkenes, aryls, and alkynyls (e.g., R 7 Br) yielding the 7-substituted sancycline compound (1E).
  • 4-dedimethylamino tetracycline compounds of the invention wherein R 7 is a carbamate or a urea derivative can be synthesized using the following protocol.
  • 4-Dedimethylamino sancycline (2A) is treated with NaNO 2 under acidic conditions forming 7-nitro 4-dedimethylamino sancycline (2B) in a mixture of positional isomers.
  • 7-nitro 4-dedimethylamino sancycline (2B) is then treated with H 2 gas and a platinum catalyst to form the 7-amino 4-dedimethylamino sancycline derivative (2C).
  • 4-dedimethylamino tetracycline compounds of the invention wherein R 7 is a heterocyclic (i.e. thiazole) substituted amino group can be synthesized using the above protocol.
  • 7-amino 4-dedimethylamino sancycline (3A) is reacted with Fmoc-isothiocyanate (3B) to produce the protected thiourea (3C).
  • the protected thiourea (3C) is then deprotected yielding the active 4-dedimethylamino sancycline thiourea (3D) compound.
  • the 4-dedimethylamino sancycline thiourea (3D) is reacted with an ⁇ -haloketone (3E) to produce a thiazole substituted 7-amino 4-dedimethylamino sancycline (3F).
  • Alkenyl substituted 4-dedimethylamino tetracycline compounds such as 7-alkynyl 4-dedimethylamino sancycline (4A) and 7-alkenyl 4-dedimethylamino sancycline (4B), can be hydrogenated to form alkyl substituted 4-dedimethylamino tetracycline compounds (e.g., 7-alkyl 4-dedimethylamino sancycline, 4C).
  • Scheme 4 depicts the selective hydrogenation of the 7- position double or triple bond, in saturated methanol and hydrochloric acid solution with a palladium/carbon catalyst under pressure, to yield the product.
  • a 9-position double or triple bond can be treated in a similar manner.
  • 7-iodo 4-dedimethylamino sancycline (5B) can then be purified using standard techniques known in the art.
  • 7-iodo 4-dedimethylamino sancycline (5B) is treated with an aqueous base (e.g., Na 2 CO 3 ) and an appropriate boronic acid (5C) and under an inert atmosphere.
  • the reaction is catalyzed with a palladium catalyst (e.g., Pd(OACc) 2 ).
  • the product (5D) can be purified by methods known in the art (such as HPLC).
  • Other 7-aryl and alkynyl tetracycline compounds can be synthesized using similar protocols.
  • the substituted 4-dedimethylamino tetracycline compounds of the invention can also be synthesized using Stille cross couplings. Stille cross couplings can be performed using an appropriate tin reagent (e.g., R-SnBu 3 ) and a halogenated 4-dedimethylamino tetracycline compound, (e.g., 7-iodo 4-dedimethylamino sancycline).
  • an appropriate tin reagent e.g., R-SnBu 3
  • a halogenated 4-dedimethylamino tetracycline compound e.g., 7-iodo 4-dedimethylamino sancycline.
  • the tin reagent and the iodo 4-dedimethylamino sancycline compound can be treated with a palladium catalyst (e.g., Pd(PPh 3 ) 2 Cl 2 or Pd(AsPh 3 ) 2 Cl 2 ) and, optionally, with an additional copper salt, e.g., CuI.
  • a palladium catalyst e.g., Pd(PPh 3 ) 2 Cl 2 or Pd(AsPh 3 ) 2 Cl 2
  • an additional copper salt e.g., CuI
  • aryl derivatives formed by Suzuki or Stille couplings can be further derivitized.
  • a formyl aryl 4-dedimethylamino sancycline (6A), an amine, and a solvent e.g., 1,2 dichloroethane
  • a reducing agent e.g., NaBH(OAc) 3 .
  • the reaction is allowed to proceed proceed to completion to yield the product (6B).
  • the product is purified and characterized using standard methods.
  • the compounds of the invention can also be synthesized using Heck-type cross coupling reactions.
  • Heck-type cross-couplings can be performed by suspending a halogenated tetracycline compound (e.g., 7-iodo 4-dedimethylamino sancycline, 7A) and an appropriate palladium or other transition metal catalyst (e.g., Pd(OAc) 2 and CuI) in an appropriate solvent (e.g., degassed acetonitrile).
  • a reactive alkene (7B) or alkyne (7D), and triethylamine are then added and the mixture is heated for several hours, before being cooled to room temperature.
  • the resulting 7-substituted alkenyl (7C) or 7-substituted alkynyl (7E) 4-dedimethylamino tetracycline compound can then be purified using techniques known in the art.
  • 7,9-substituted 4-dedimethylamino tetracycline compounds can be synthesized as shown in Scheme 9 for 4-dedimethylamino sancycline.
  • 4-Dedimethylamino sancycline (9A) is treated with sulfuric acid and sodium nitrate.
  • the resulting product is 7,9-nitro 4-dedimethylamino sancycline (9B).
  • the nitro 4-dedimethylamino sancycline compound is then treated with hydrogen gas and a platinum catalyst to yield the 7,9-amino 4-dedimethylamino sancycline compound, 9C.
  • the 7,9-amino 4-dedimethylamino sancycline compound is treated with HONO, to yield the diazonium salt (9D).
  • the salt can subsequently be treated with numerous compounds possessing an alkene or ⁇ bond functional group such as alkenes, aryls, and alkynyls (e.g., RBr) yielding the 7,9-substituted 4-dedimethylamino sancycline compound (9E).
  • the 13-substituted 4-dedimethylamino methacycline compounds of the invention can be synthesized by methods known in the art and/or as described herein.
  • Scheme 10 a general synthetic scheme for the synthesis of 13-substituted 4-dedimethylamino methacycline compounds is shown.
  • 4-dedimethylamino methacycline is coupled with a boronic acid in the presence of a transition metal catalyst.
  • aryl coupling reactions known in the art may also be used.
  • the 4-dedimethylamino methacycline is reacted with a phenylboronic acid in the presence of a palladium catalyst such as Pd(OAc) 2 .
  • a palladium catalyst such as Pd(OAc) 2 .
  • the resulting compound can then be purified using techniques known in the art such as preparative HPLC and characterized.
  • the synthesis of the compounds of the invention are described in more detail in Example 4.
  • 8-Substituted 4-dedimethylamino tetracycline compounds of the invention can be synthesized by transition metal catalyzed coupling of tetracyclines halogenated at the 8- position.
  • transition metal catalysis many reactions between aryl halides and various reactive species have been developed using transition metal catalysis.
  • Coupling of aryl halides or triflates with main group organometallics with oxidate addition-transmetallation-reductive elimination reactions has been developed and occurs using a wide range of catalysts, such as Pd(Pd 3 ) 4 , Pd(dba) 2 , PdCl 2 , Pd(OAc) 2 , and PdCl 2 (CH 3 CN) 2 .
  • Ligands such as PPh 3 or AsPh 3 may be added to form catalysts in situ with palladium species such as Pd(dba) 2 or PdCl 2 .
  • copper salts such as CuCN or CuI may also be added to further enhance the reaction.
  • Scheme 12 An example of a coupling using a halogenated tetracycline compound is shown in Scheme 12. In Scheme 12, X is bromine or chlorine.
  • the substituted tetracycline compounds of the invention can be synthesized using organotin reagents, halogenated or triflate tetracycline compounds, and an appropriate catalyst (e.g., palladium).
  • organotin reagents include, for example, ethenyl tributyltin, ethynyl tributyltin, phenyl tributyltin, ethenyl trimethyl tin, ethynyl trimethyl tin, etc.
  • Stille type couplings are run by adding the transition metal (e.g., palladium) catalyst to a solution of the halogenated or triflate tetracycline compound and the organotin reagent in polar solvents.
  • transition metal e.g., palladium
  • Stille type couplings with alkynyl and alkenyl tin reagents are shown in Scheme 13, wherein X is a halogen or a triflate group.
  • alkyl includes saturated aliphatic groups, including straight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups (cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • straight-chain alkyl groups e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,
  • alkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkyl has 6 or fewer carbon atoms in its backbone (e.g., C 1 -C 6 for straight chain, C 3 -C 6 for branched chain), and more preferably 4 or fewer.
  • preferred cycloalkyls have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C 1 -C 6 includes alkyl groups containing 1 to 6 carbon atoms.
  • alkyl includes both "unsubstituted alkyls" and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sul
  • Cycloalkyls can be further substituted, e.g., with the substituents described above.
  • An "alkylaryl” or an “arylalkyl” moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • the term “alkyl” also includes the side chains of natural and unnatural amino acids.
  • aryl includes groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole, imidazole, triazole, tetrazole, pyrazole, oxazole, isooxazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • aryl includes multicyclic aryl groups, e.g., tricyclic, bicyclic, e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline, isoquinoline, napthridine, indole, benzofuran, purine, benzofuran, deazapurine, or indolizine.
  • aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles", “heterocycles,” “heteroaryls” or “heteroaromatics”.
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl (alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
  • alkenyl includes straight-chain alkenyl groups (e.g., ethylenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonen
  • alkenyl further includes alkenyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkenyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • cycloalkenyl groups may have from 3-8 carbon atoms in their ring structure, and more preferably have 5 or 6 carbons in the ring structure.
  • C 2 -C 6 includes alkenyl groups containing 2 to 6 carbon atoms.
  • alkenyl includes both "unsubstituted alkenyls" and “substituted alkenyls”, the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
  • alkynyl further includes alkynyl groups which include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.
  • a straight chain or branched chain alkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • the term C 2 -C 6 includes alkynyl groups containing 2 to 6 carbon atoms.
  • alkynyl includes both "unsubstituted alkynyls" and “substituted alkynyls”, the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to five carbon atoms in its backbone structure.
  • Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-5 carbon atoms.
  • acyl includes compounds and moieties which contain the acyl radical (CH 3 CO-) or a carbonyl group. It includes substituted acyl moieties.
  • substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including
  • acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
  • the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
  • alkoxyalkyl examples include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
  • alkoxy includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate
  • amine or “amino” includes compounds where a nitrogen atom is covalently bonded to at least one carbon or heteroatom.
  • the term includes “alkyl amino” which comprises groups and compounds wherein the nitrogen is bound to at least one additional alkyl group.
  • dialkyl amino includes groups wherein the nitrogen atom is bound to at least two additional alkyl groups.
  • arylamino and “diarylamino” include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively.
  • alkylarylamino alkylaminoaryl or “arylaminoalkyl” refers to an amino group which is bound to at least one alkyl group and at least one aryl group.
  • alkaminoalkyl refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.
  • amide includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.
  • the term includes "alkaminocarbonyl” or “alkylaminocarbonyl” groups which include alkyl, alkenyl, aryl or alkynyl groups bound to an amino group bound to a carbonyl group. It includes arylaminocarbonyl and arylcarbonylamino groups which include aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.
  • alkylaminocarbonyl alkenylaminocarbonyl
  • alkynylaminocarbonyl alkynylaminocarbonyl
  • arylaminocarbonyl alkylcarbonylamino
  • alkenylcarbonylamino alkynylcarbonylamino
  • arylcarbonylamino alkylcarbonylamino
  • alkenylcarbonylamino alkynylcarbonylamino
  • arylcarbonylamino alkylcarbonylamino
  • carbonyl or “carboxy” includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom.
  • the carbonyl can be further substituted with any moiety which allows the compounds of the invention to perform its intended function.
  • carbonyl moieties may be substituted with alkyls, alkenyls, alkynyls, aryls, alkoxy, aminos, etc.
  • moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc.
  • thiocarbonyl or "thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • ether includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms.
  • alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
  • esters includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group.
  • ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
  • alkyl, alkenyl, or alkynyl groups are as defmed above.
  • thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or hetero atoms.
  • examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls.
  • alkthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
  • alkthioalkenyls and alkthioalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
  • hydroxy or "hydroxyl” includes groups with an -OH or -O - .
  • halogen includes fluorine, bromine, chlorine, iodine, etc.
  • perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
  • polycyclyl or “polycyclic radical” refer to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl, arylalkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkyl carbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amido, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoy
  • heteroatom includes atoms of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
  • prodrug moiety includes moieties which can be metabolized in vivo to a hydroxyl group and moieties which may advantageously remain esterified in vivo.
  • the prodrugs moieties are metabolized in vivo by esterases or by other mechanisms to hydroxyl groups or other advantageous groups.
  • Examples of prodrugs and their uses are well known in the art (See, e.g. , Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19 ).
  • the prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent.
  • Hydroxyl groups can be converted into esters via treatment with a carboxylic acid.
  • prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkylamino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower-alkyl amides, di-
  • the structure of some of the tetracycline compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof.
  • the invention also pertains to methods for treating a tetracycline responsive states in subjects, by administering to a subject an effective amount of a 4-dedimethylamino tetracycline compound of the invention (e.g., of Formula I, II, III, IV, V, VI, VII, VIII or Table 2), such that the tetracycline responsive state is treated.
  • a 4-dedimethylamino tetracycline compound of the invention e.g., of Formula I, II, III, IV, V, VI, VII, VIII or Table 2
  • treating includes curing as well as ameliorating at least one symptom of the state, disease or disorder, e.g., the tetracycline compound responsive state.
  • tetracycline compound responsive state or “tetracycline responsive state” includes states which can be treated, prevented, or otherwise ameliorated by the administration of a tetracycline compound of the invention, e.g., a 4-dedimethylamino tetracycline compound (e.g., of Formula I, II, III, IV, V, VI, VII, VIII or Table 2).
  • Tetracycline compound responsive states include bacterial infections (including those which are resistant to other tetracycline compounds), cancer (e.g., prostate, breast, colon, lung melanoma and lymph cancers and other disorders charboatized by unwanted cellular proliferation, including, but not limited to, those described in U.S.
  • Compounds of the invention can be used to prevent or control important mammalian and veterinary diseases such as diarrhea, urinary tract infections, infections of skin and skin structure, ear, nose and throat infections, wound infection, mastitis and the like.
  • the tetracycline responsive state is not a bacterial infection.
  • the tetracycline compounds of the invention are essentially non-antibacterial.
  • non-antibacterial tetracycline compounds of the invention may have MIC values greater than about 4 ⁇ g/ml (as measured by assays known in the art and/or the assay given in Example 6).
  • Tetracycline compound responsive states also include inflammatory process associated states (IPAF).
  • inflammatory process associated state includes states in which inflammation or inflammatory factors (e.g., matrix metalloproteinases (MMPs), nitric oxide (NO), TNF, interleukins, plasma proteins, cellular defense systems, cytokines, lipid metabolites, proteases, toxic radicals, adhesion molecules, etc .) are involved or are present in an area in aberrant amounts, e.g., in amounts which may be advantageous to alter, e.g., to benefit the subject.
  • MMPs matrix metalloproteinases
  • NO nitric oxide
  • TNF interleukins
  • plasma proteins e.g., plasma proteins
  • cellular defense systems e.g., cytokines, lipid metabolites, proteases, toxic radicals, adhesion molecules, etc .
  • the inflammatory process is the response of living tissue to damage.
  • the cause of inflammation may be due to physical damage, chemical substances, micro
  • IPAF's include inflammatory disorders. Inflammatory disorders are generally characterized by heat, redness, swelling, pain and loss of function. Examples of causes of inflammatory disorders include, but are not limited to, microbial infections (e.g. , bacterial and fungal infections), physical agents (e.g., bums, radiation, and trauma chemical agents (e.g. , toxins and caustic substances), tissue necrosis and various types of immunologic reactions.
  • inflammatory disorders include, but are not limited to, osteoarthritis, rheumatoid arthritis, acute and chronic infections (bacterial and fungal, including diphtheria and pertussis); acute and chronic bronchitis, sinusitis, and upper respiratory infections, including the common cold; acute and chronic gastroenteritis and colitis; acute and chronic cystitis and urethritis; acute and chronic dermatitis; acute and chronic conjunctivitis; acute and chronic serositis (pericarditis, peritonitis, synovitis, pleuritis and tendinitis); uremic pericarditis; acute and chronic cholecystis; acute and chronic vaginitis; acute and chronic uveitis; drug reactions; insect bites; burns (thermal, chemical, and electrical); and sunburn.
  • osteoarthritis bacterial and fungal, including diphtheria and pertussis
  • acute and chronic bronchitis sinusitis, and upper respiratory infections, including the common cold
  • Tetracycline compound responsive states also include NO associated states.
  • NO associated state includes states which involve or are associated with nitric oxide (NO) or inducible nitric oxide synthase (iNOS).
  • NO associated state includes states which are characterized by aberrant amounts of NO and/or iNOS.
  • the NO associated state can be treated by administering tetracycline compounds of the invention (e.g., of Formula I, II, III, IV, V, VI, VII, VIII or Table 2).
  • the invention includes 7-substituted 4-dedimethylamino tetracyclines.
  • the disorders, diseases and states described in U.S. Patents Nos. 6,231,894 ; 6,015,804 ; 5,919,774 ; and 5,789,395 are also included as NO associated states. The entire contents of each of these patents are hereby incorporated herein by reference.
  • NO associated states include, but are not limited to, malaria, senescence, diabetes, vascular stroke, neurodegenerative disorders (Alzheimer's disease & Huntington's disease), cardiac disease ( re-perfusion-associated injury following infarction), juvenile diabetes, inflammatory disorders, osteoarthritis, rheumatoid arthritis, acute and chronic infections (bacterial and fungal, including diphtheria and pertussis); acute and chronic bronchitis, sinusitis, and upper respiratory infections, including the common cold; acute and chronic gastroenteritis and colitis; acute and chronic cystitis and urethritis; acute and chronic dermatitis; acute and chronic conjunctivitis; acute and chronic serositis (pericarditis, peritonitis, synovitis, pleuritis and tendinitis); uremic pericarditis; acute and chronic cholecystis; acute and chronic vaginitis; acute and chronic uveitis; drug reactions; insect bites; burns (
  • MMPAS matrix metalloproteinase associated states
  • MMPAS include states charachterized by abberrant amounts of MMPs or MMP activity. These are also include as tetracycline compound responsive states which may be treated using compounds of the invention, e.g., 4-dedimethylamino tetracycline compounds such as those described herein (e.g., of Formula I, II, III, IV, V, VI, VII, VIII or Table 2).
  • MMPs matrix metalloproteinase associated states
  • arteriosclerosis arteriosclerosis
  • corneal ulceration emphysema
  • osteoarthritis multiple sclerosis( Liedtke et al., Ann. Neural. 1998, 44:35-46 ; Chandler et al., J. Neuroimmunol.1997, 72:155-71 ), osteosarcoma, osteomyelitis, bronchiectasis, chronic pulmonary obstructive disease, skin and eye diseases, periodontitis, osteoporosis, rheumatoid arthritis, ulcerative colitis, inflammatory disorders, tumor growth and invasion ( Stetler-Stevenson et al., Annu.
  • MMPAS include those described in U.S. Pat. Nos.
  • the tetracycline compound responsive state is cancer.
  • cancers which the tetracycline compounds of the invention may be useful to treat include all solid tumors, i.e., carcinomas e.g., adenocarcinomas, and sarcomas.
  • Adenocarcinomas are carcinomas derived from glandular tissue or in which the tumor cells form recognizable glandular structures.
  • Sarcomas broadly include tumors whose cells are embedded in a fibrillar or homogeneous substance like embryonic connective tissue.
  • carcinomas which may be treated using the methods of the invention include, but are not limited to, carcinomas of the prostate, breast, ovary, testis, lung, colon, and breast.
  • the methods of the invention are not limited to the treatment of these tumor types, but extend to any solid tumor derived from any organ system.
  • treatable cancers include, but are not limited to, colon cancer, bladder cancer, breast cancer, melanoma, ovarian carcinoma, prostatic carcinoma, lung cancer, and a variety of other cancers as well.
  • the methods of the invention also cause the inhibition of cancer growth in adenocarcinomas, such as, for example, those of the prostate, breast, kidney, ovary, testes, and colon.
  • the tetracycline responsive state of the invention is cancer.
  • the invention pertains to a method for treating a subject suffering or at risk of suffering from cancer, by administering an effective amount of a substituted tetracycline compound, such that inhibition cancer cell growth occurs, i.e., cellular proliferation, invasiveness, metastasis, or tumor incidence is decreased, slowed, or stopped.
  • the inhibition may result from inhibition of an inflammatory process, down-regulation of an inflammatory process, some other mechanism, or a combination of mechanisms.
  • the tetracycline compounds may be useful for preventing cancer recurrence, for example, to treat residual cancer following surgical resection or radiation therapy.
  • the tetracycline compounds useful according to the invention are especially advantageous as they are substantially non-toxic compared to other cancer treatments.
  • the compounds of the invention are administered in combination with standard cancer therapy, such as, but not limited to, chemotherapy.
  • the language "in combination with" another therapeutic agent or treatment includes co-administration of the tetracycline compound, (e.g. , inhibitor) and with the other therapeutic agent or treatment, administration of the tetracycline compound first, followed by the other therapeutic agent or treatment and administration of the other therapeutic agent or treatment first, followed by the tetracycline compound.
  • the other therapeutic agent may be any agent which is known in the art to treat, prevent, or reduce the symptoms of an IPAS.
  • the other therapeutic agent may be any agent of benefit to the patient when administered in combination with the administration of an tetracycline compound.
  • the cancers treated by methods of the invention include those described in U.S. Patent Nos. 6,100,248 ; 5,843,925 ; 5,837,696 ; or 5,668,122 , incorporated herein by reference in their entirety.
  • the tetracycline compound responsive state is diabetes, e.g., juvenile diabetes, diabetes mellitus, diabetes type I, or diabetes type II.
  • protein glycosylation is not affected by the administration of the tetracycline compounds of the invention.
  • the tetracycline compound of the invention is administered in combination with standard diabetic therapies, such as, but not limited to insulin therapy.
  • the IPAS includes disorders described in U.S. Patents Nos. 5,929,055 ; and 5,532,227 , incorporated herein by reference in their entirety.
  • the tetracycline compound responsive state is a bone mass disorder.
  • Bone mass disorders include disorders where a subjects bones are disorders and states where the formation, repair or remodeling of bone is advantageous.
  • bone mass disorders include osteoporosis (e.g., a decrease in bone strength and density), bone fractures, bone formation associated with surgical procedures (e.g. , facial reconstruction), osteogenesis imperfecta (brittle bone disease), hypophosphatasia, Paget's disease, fibrous dysplasia, osteopetrosis, myeloma bone disease, and the depletion of calcium in bone, such as that which is related to primary hyperparathyroidism.
  • Bone mass disorders include all states in which the formation, repair or remodeling of bone is advantageous to the subject as well as all other disorders associated with the bones or skeletal system of a subject which can be treated with the tetracycline compounds of the invention.
  • the bone mass disorders include those described in U.S. Patents Nos. 5,459,135 ; 5,231,017 ; 5,998,390 ; 5,770,588 ; RE 34,656 ; 5,308,839 ; 4,925,833 ; 3,304,227 ; and 4,666,897 , each of which is hereby incorporated herein by reference in its entirety.
  • the tetracycline compound responsive state is acute lung injury.
  • Acute lung injuries include adult respiratory distress syndrome (ARDS), post-pump syndrome (PPS), and trauma.
  • Trauma includes any injury to living tissue caused by an extrinsic agent or event. Examples of trauma include, but are not limited to, crush injuries, contact with a hard surface, or cutting or other damage to the lungs.
  • the invention also pertains to a method for treating acute lung injury by administering a substituted tetracycline compound of the invention.
  • the tetracycline responsive states of the invention also include chronic lung disorders.
  • the invention pertains to methods for treating chronic lung disorders by administering a tetracycline compound, such as those described herein.
  • the method includes administering to a subject an effective amount of a substituted tetracycline compound such that the chronic lung disorder is treated.
  • chronic lung disorders include, but are not limited, to asthma, cystic fibrosis, and emphesema.
  • the tetracycline compounds of the invention used to treat acute and/or chronic lung disorders such as those described in U.S. Patents No. 5,977,091 ; 6,043,231 ; 5,523,297 ; and 5,773,430 , each of which is hereby incorporated herein by reference in its entirety.
  • the tetracycline compound responsive state is ischemia, stroke, or ischemic stroke.
  • the invention also pertains to a method for treating ischemia, stroke, or ischemic stroke by administering an effective amount of a substituted tetracycline compound of the invention.
  • the tetracycline compounds of the invention are used to treat such disorders as described in U.S. Patents No. 6,231,894 ; 5,773,430 ; 5,919,775 or 5,789,395 , incorporated herein by reference.
  • the tetracycline compound responsive state is a skin wound.
  • the invention also pertains, at least in part, to a method for improving the healing response of the epithelialized tissue (e.g., skin, mucusae) to acute traumatic injury (e.g., cut, burn, scrape, etc.).
  • the method may include using a tetracycline compound of the invention (which may or may not have antibacterial activity) to improve the capacity of the epithelialized tissue to heal acute wounds.
  • the method may increase the rate of collagen accumulation of the healing tissue.
  • the method may also decrease the proteolytic activity in the epthithelialized tissue by decreasing the collagenolytic and/or gellatinolytic activity of MMPs.
  • the tetracycline compound of the invention is administered to the surface of the skin (e.g., topically).
  • the tetracycline compound of the invention used to treat a skin wound, and other such disorders as described in, for example, U.S. Patent Nos. 5,827,840 ; 4,704,383 ; 4,935,412 ; 5,258,371 ; 5,308,83915 , 459,135 ; 5,532,227 ; and 6,015,804 ; each of which is incorporated herein by reference in its entirety.
  • the tetracycline compound responsive state is an aortic or vascular aneurysm in vascular tissue of a subject (e.g., a subject having or at risk of having an aortic or vascular aneurysm, etc.).
  • the tetracycline compound may by effective to reduce the size of the vascular aneurysm or it may be administered to the subject prior to the onset of the vascular aneurysm such that the aneurysm is prevented.
  • the vascular tissue is an artery, e.g., the aorta, e.g., the abdominal aorta.
  • the tetracycline compounds of the invention are used to treat disorders described in U.S. Patent Nos. 6,043,225 and 5,834,449 , incorporated herein by reference in their entirety.
  • Bacterial infections may be caused by a wide variety of gram positive and gram negative bacteria.
  • the compounds of the invention are useful as antibiotics against organisms which are resistant to other tetracycline compounds.
  • the antibiotic activity of the tetracycline compounds of the invention may be determined using the method discussed in Example 2, or by using the in vitro standard broth dilution method described in Waitz, J.A., National Commission for Clinical Laboratory Standards, Document M7-A2, vol. 10, no. 8, pp. 13-20, 2nd edition, Villanova, PA (1990 ).
  • the tetracycline compounds may also be used to treat infections traditionally treated with tetracycline compounds such as, for example, rickettsiae; a number of gram-positive and gram-negative bacteria; and the agents responsible for lymphogranuloma venereum, inclusion conjunctivitis, psittacosis.
  • the tetracycline compounds may be used to treat infections of, e.g., K. pneumoniae, Salmonella, E. hirae, A. baumanii, B. catarrhalis, H. influenzae, P. aeruginosa, E. faecium, E. coli, S. aureus or E. faecalis.
  • the tetracycline compound is used to treat a bacterial infection that is resistant to other tetracycline antibiotic compounds.
  • the tetracycline compound of the invention may be administered with a pharmaceutically acceptable carrier.
  • the language "effective amount" of the compound is that amount necessary or sufficient to treat or prevent a tetracycline compound responsive state.
  • the effective amount can vary depending on such factors as the size and weight of the subject, the type of illness, or the particular tetracycline compound. For example, the choice of the tetracycline compound can affect what constitutes an "effective amount".
  • One of ordinary skill in the art would be able to study the aforementioned factors and make the determination regarding the effective amount of the tetracycline compound without undue experimentation.
  • the invention also pertains to methods of treatment against microorganism infections and associated diseases.
  • the methods include administration of an effective amount of one or more tetracycline compounds to a subject.
  • the subject can be either a plant or, advantageously, an animal, e.g., a mammal, e.g., a human.
  • one or more tetracycline compounds of the invention may be administered alone to a subject, or more typically a compound of the invention will be administered as part of a pharmaceutical composition in mixture with conventional excipient, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, oral or other desired administration and which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • conventional excipient i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, oral or other desired administration and which do not deleteriously react with the active compounds and are not deleterious to the recipient thereof.
  • the invention also pertains to pharmaceutical compositions comprising a therapeutically effective amount of a 4-dedimethylamino tetracycline compound (e.g., a compound of Formula I, II, III, IV, V, VI, VII, VIII or Table 2) and, optionally, a pharmaceutically acceptable carrier.
  • a 4-dedimethylamino tetracycline compound e.g., a compound of Formula I, II, III, IV, V, VI, VII, VIII or Table 2
  • a pharmaceutically acceptable carrier e.g., a compound of Formula I, II, III, IV, V, VI, VII, VIII or Table 2
  • pharmaceutically acceptable carrier includes substances capable of being coadministered with the tetracycline compound(s), and which allow both to perform their intended function, e.g., treat or prevent a tetracycline responsive state.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds of the invention.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the active compounds of the invention.
  • the tetracycline compounds of the invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of the tetracycline compounds of the invention that are basic in nature are those that form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate
  • salts must be pharmaceutically acceptable for administration to a subject, e.g., a mammal
  • the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
  • the preparation of other tetracycline compounds of the invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
  • the tetracycline compounds of the invention that are acidic in nature are capable of forming a wide variety of base salts.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those tetracycline compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to those derived from such pharmaceutically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
  • the pharmaceutically acceptable base addition salts of tetracycline compounds of the invention that are acidic in nature may be formed with pharmaceutically acceptable cations by conventional methods.
  • these salts may be readily prepared by treating the tetracycline compound of the invention with an aqueous solution of the desired pharmaceutically acceptable cation and evaporating the resulting solution to dryness, preferably under reduced pressure.
  • a lower alkyl alcohol solution of the tetracycline compound of the invention may be mixed with an alkoxide of the desired metal and the solution subsequently evaporated to dryness.
  • tetracycline compounds of the invention and pharmaceutically acceptable salts thereof can be administered via either the oral, parenteral or topical routes.
  • these compounds are most desirably administered in effective dosages, depending upon the weight and condition of the subject being treated and the particular route of administration chosen. Variations may occur depending upon the species of the subject being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
  • compositions of the invention may be administered alone or in combination with other known compositions for treating tetracycline responsive states in a subject, e.g., a mammal.
  • Preferred mammals include pets (e.g., cats, dogs, ferrets, etc.), farm animals (cows, sheep, pigs, horses, goats, etc.), lab animals (rats, mice, monkeys, etc.), and primates (chimpanzees, humans, gorillas).
  • the language "in combination with" a known composition is intended to include simultaneous administration of the composition of the invention and the known composition, administration of the composition of the invention first, followed by the known composition and administration of the known composition first, followed by the composition of the invention. Any of the therapeutically composition known in the art for treating tetracycline responsive states can be used in the methods of the invention.
  • the tetracycline compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes previously mentioned, and the administration may be carried out in single or multiple doses.
  • the novel therapeutic agents of this invention can be administered advantageously in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • oral pharmaceutical compositions can be suitably sweetened and/or flavored.
  • the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
  • tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
  • the aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic.
  • These aqueous solutions are suitable for intravenous injection purposes.
  • the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
  • suitable preparations include solutions, preferably oily or aqueous solutions as well as suspensions, emulsions, or implants, including suppositories.
  • Therapeutic compounds may be formulated in sterile form in multiple or single dose formats such as being dispersed in a fluid carrier such as sterile physiological saline or 5% saline dextrose solutions commonly used with injectables.
  • topical administration examples include transdermal, buccal or sublingual application.
  • therapeutic compounds can be suitably admixed in a pharmacologically inert topical carrier such as a gel, an ointment, a lotion or a cream.
  • topical carriers include water, glycerol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, or mineral oils.
  • topical carriers are liquid petrolatum, isopropylpalmitate, polyethylene glycol, ethanol 95%, polyoxyethylene monolauriate ,5% in water, sodium lauryl sulfate 5% in water, and the like.
  • materials such as anti-oxidants, humectants, viscosity stabilizers and the like also may be added if desired.
  • tablets, dragees or capsules having talc and/or carbohydrate carrier binder or the like are particularly suitable, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
  • Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • the therapeutic methods of the invention also will have significant veterinary applications, e.g. for treatment of livestock such as cattle, sheep, goats, cows, swine and the like; poultry such as chickens, ducks, geese, turkeys and the like; horses; and pets such as dogs and cats.
  • livestock such as cattle, sheep, goats, cows, swine and the like
  • poultry such as chickens, ducks, geese, turkeys and the like
  • horses such as dogs and cats.
  • the compounds of the invention may be used to treat non-animal subjects, such as plants.
  • compounds of the invention for treatment can be administered to a subject in dosages used in prior tetracycline therapies. See, for example, the Physicians' Desk Reference.
  • a suitable effective dose of one or more compounds of the invention will be in the range of from 0.01 to 100 milligrams per kilogram of body weight of recipient per day, preferably in the range of from 0.1 to 50 milligrams per kilogram body weight of recipient per day, more preferably in the range of 1 to 20 milligrams per kilogram body weight of recipient per day.
  • the desired dose is suitably administered once daily, or several sub-doses, e.g. 2 to 5 sub-doses, are administered at appropriate intervals through the day, or other appropriate schedule.
  • the invention also pertains to the use of a tetracycline compound of Formula I, II, III, IV, V, VI, VII, VIII or Table 2 for the preparation of a medicament.
  • the medicament may include a pharmaceutically acceptable carrier and the tetracycline compound is an effective amount, e.g. , an effective amount to treat a tetracycline responsive state.
  • the methanolic solution is added slowly to a rapidly stirring solution of the product in diethyl ether to form a greenish brown precipitate.
  • the 7-iodo isomer of 4-dedimethylamino sancycline is purified by treating the 7-iodo 4-dedimethylamino product with activated charcoal., filtering through Celite, and subsequent removal of the solvent in vacuo to produce the 7-isomer compound as a pure solid.
  • NN-Dimethylglycine (1.2 mmol) is dissolved in DMF (5 mL) and O- Benzotriazol-1-yl- N , N, N', N', -tetramethyluronium hexafluorophosphate (HBTU, 1.2 mmol) was added. The solution is then stirred for 5 minutes at room temperature. To this solution, 7-amino 4-dedimethylamino sancycline (1 mmol, 16A) was added, followed by the addition of diisopropylethyl amine (DIEA, 1.2 mmol). The reaction is then stirred at room temperature for 2 hours. The solvent, DMF, is removed on vaccum. The crude material is dissolved in 5 mL of MeOH and filtered using autovials and purified using preparative HPLC.
  • HBTU O- Benzotriazol-1-yl- N , N, N', N', -tetramethyluronium hexa
  • the reaction is purged with a slow steam of argon gas, with stirring, for 5 minutes before the addition (in one portion as a solid) of N-methylsulphonamidopropargyl amine (17B).
  • the sulphonamide is prepared by a method known in the art ( J.Med.Chem 31(3) 1988; 577-82 ). This is followed by one milliliter of triethylamine (1 ml; 0.726 mg; 7.175 mmoles) and the reaction is stirred, under an argon atmosphere, for approximately 1.0 hour at ambient temperature. The reaction mixture is suctioned filtered through a pad of diatomaceous earth and washed with acetonitrile.
  • the filtrates are reduced to dryness under vacuo and the residue is treated with a dilute solution of trifluroroacetic acid in acetonitrile to adjust the pH to approximately 2.
  • the residue is treated with more dilute trifluoroacetic acid in acetonitrile, resulting in the formation of a precipitate, which is removed via suction filtration.
  • the crude filtrates are purified utilizing reverse phase HPLC with DVB as the solid phase; and a gradient of 1:1 methanol/acetonitrile 1% trifluoroacetic acid and 1% trifluoroacetic acid in water.
  • the appropriate fractions are reduced to dryness under reduced pressure and solid collected.
  • the product is characterized via 1 H NMR, mass spectrogram and LC reverse phase.
  • 2-Methoxy-5-formylphenyl boronic acid (18B, 333mg, 1.83mmol) is dissolved in MeOH (5mL) and added to reaction flask. The flask is then purged again with argon for 10 minutes. The reaction is monitored to completion within 3 hours. The contents of the flask are filtered through filter paper and the remaining solvent is evacuated. To make the hydrochloric acid salt, the residue is dissolved in MeOH (sat. HCl). The solution is then filtered and the solvent was evacuated. The product is then characterized by 1 H NMR, LC-MS.
  • the aldehyde (19A, 1g, 1.82mmol), dimethylamine HCl (19B, 297 mg, 3.64 mmol), triethylamine (506 ⁇ L, 3.64 mmol), and 1,2-DCE (7 mL) are combined in a 40 mL vial. The contents are dissolved within several minutes of shaking or stirring. Sodium triacetoxyborohydride (772 mg, 3.64 mmol) is then added as a solid. The reaction is monitored by HPLC and LC-MS and is complete within 3 hours. The reaction is quenched with MeOH (2 0mL) and the solvent is subsequently evacuated. The residue is redissolved in 3mL DMF and separated on a C-18 column.
  • the 7-iodo isomer of sancycline is purified by treating the 7-iodo product with activated charcoal., filtering through Celite, and subsequent removal of the solvent in vacuo to produce the 7-isomer compound as a pure solid.
  • 9-t-butyl-4-dedimethylamino sancycline (26A, 1.13 g, 2 mmol) is dissolved in 5 ml methanesulfonic acid (0.448, 2 mmol).
  • N-iodosuccinimide (26B) is added at room temperature over one hour in four portions.
  • the product (26C) is precipitated with diethyl ether, filtered off and used in other reaction without further purification.
  • the reaction is slowly quenched into 2L of ice cold water containing [17.88g;1134.1mM] of sodium thiosulfate with rapid stirring. This quench is stirred for approximately 30 minutes at ambient temperature.
  • the aqueous layer is then extracted with 6x200ml of ethyl acetate before the aqueous was poured onto [259.8g;3.08M] of sodium hydrogen carbonate containing 300ml of n-butanol.
  • the phases are split and the aqueous extracted with 4x250ml of n-butanol.
  • the organic fractions are combined and washed with 3x250ml of water and once with 250ml of saturated brine.
  • the resulting organic phase is reduced to dryness under reduced pressure.
  • the residue is suspended in methanol ( ⁇ 600ml) and anhydrous HCl gas is bubbled into this mixture until solution occurred This solution is reduced to dryness under reduced pressure.
  • the filtrates are reduced to dryness under reduced pressure.
  • the resulting material is triturated with 300ml of methyl t-butyl ether and isolated via filtration. This material is redissolved in 300ml of methanol and treated with 0.5g of wood carbon, filtered and filtrates reduced to dryness under reduced pressure.
  • the material is again powdered under methyl t-butyl ether, isolated via suction filtration and washed with more ether, and finally hexanes.
  • the material is vacuum dried to give the product.
  • reaction vessel In a clean, dry reaction vessel, is placed 9-iodo 4-dedimethylamino minocycline [0.762mmoles]bis HCl salt, palladium (II) acetate [17.2mg; 0.076mmoles] along with 10ml of reagent grade methanol. The solution is immediately purged, with stirring, with a stream of argon gas for approximately 5 minutes. The reaction vessel is brought to reflux and to it is sequentially added via syringe 2M potassium carbonate solution [1.91ml; 3.81mmoles], followed by a solution of p-carboxyphenyl boronic acid [238.3mg; 1.53mmoles]in 5ml of reagent DMF.
  • Both of these solutions are previously degassed with argon gas for approximately 5minutes.
  • the reaction is heated for 45 minutes, the progress is monitored via reverse phase HPLC.
  • the reaction is suctioned filtered through a pad of diatomaceous earth and the pad is washed with DMF.
  • the filtrates are reduced to an oil under vacuum and residue is treated with t-butylmethyl ether.
  • Crude material is purified via reverse phase HPLC on DVB utilizing a gradient of water and methanol/acetonitrile containing 1.0% trifluoroacetic acid.
  • 9-NO 2 4-dedimethylamino doxycycline (1g) is dissolved in methanol (50 ml) and poured into a Parr apparatus with 100 mg of 10% Pd/C. The reaction is charged with H 2 and shaken for 2 hours. The 9-amino 4-dedimethylamino doxycycline is separated by preparative apic purification to produce 9-NH 2 4-dedimethylamino doxycycline and 7-NH 2 4-dedimethylamino doxycycline.
  • the final cell density should be approximately 5x10 5 CFU/ml.
  • These plates are incubated at 35°C in an ambient air incubator for approximately 18 hr. The plates are read with a microplate reader and are visually inspected when necessary.
  • the MIC is defined as the lowest concentration of the tetracycline compound that inhibits growth.

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